Arylgycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds

ABSTRACT

The invention relates to new arylglycinamide derivatives of general formula I                    
     and the pharmaceutically acceptable salts thereof, wherein 
     R 1  and R 2  together with the N to which they are bound form a ring of the formula                    
      wherein 
     is 2 or 3 and 
     X denotes oxygen, N(CH 2 ) n R 6  or CR 7 R 8 , 
     and R 3   4  R 5  R 6  R 7 , R 8 , Ar and n have the meanings given in the specification, and the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin)-antagonists.

CROSS REFERENCE TO RELATED APPLICATIONS

This appliaction is a division of application Ser. No. 09/507,581, filedFeb. 18, 2000, which is division of application Ser. No. 08/930,704, §102(e) date Oct. 29, 1997, now U.S. Pat. No. 6,124,296, which is theNational Stage of International Application No. PCT/EP96/01548, filedApr. 11, 1996.

SUMMARY OF THE INVENTION

The invention relates to new arylglycinamide derivatives of generalformula I.

and the pharmaceutically acceptable salts thereof, processes forpreparing them and pharmaceutical compositions containing thesecompounds. The compounds are valuable neurokinin (tachykinin)antagonists.

DETAILED DESCRIPTION OF THE INVENTION

The abbreviations used in the specification and claims are explained asfollows:

CDI = Carbonyldiimidazole DCCI = Dicyclohexylcarbodiimide HOBt =1-Hydroxybenzotriazole THF = Tetrahydrofuran DMF = Dimethylformamide RT= Room temperature DMAP = 4-Dimethylaminopyridine TBTU =O-Benzotriazolyl-tetramethyluronium- tetrafluoroborate

In order to show the formulae, a simplified representation is used. Inthe representation of the compounds all CH₃— substituents arerepresented by a single bond, and for example the following formula

represents

The invention relates to new arylglycinamide derivatives of generalformula I

or the pharmaceutically acceptable salts thereof, wherein

Ar denotes unsubstituted or mono- to penta-substituted phenyl, orunsubstituted or mono- or di-substituted naphthyl, [in which thesubstituents of the phenyl and naphthyl independently of each otherdenote halogen (F, Cl, Br, I), OH, (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃or NR⁹R¹⁰ (wherein R⁹ and R¹⁰ independently of each other denote H,methyl or acetyl)] or Ar is phenyl substituted by —OCH₂O— or —O(CH₂)₂O—;

R¹ and R² together with the N to which they are bound form a ring of theformula

 wherein

p is 2 or 3,

X denotes oxygen, N(CH₂)_(n)R⁶ or CR⁷R⁸ wherein

n is 0, 1 or 2,

R⁶ is (C₃₋₇)cycloalkyl, phenyl or naphthyl, wherein the phenyl may bemono- to tri-substituted by halogen (F, Cl, Br, I), (C₁₋₄)alkyl,O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶ independentlyof each other denote H, methyl or acetyl);

R⁷ and R⁸ have one of the following meanings:

a) R⁷ and R⁸ represent H if R³ is unsubstituted or substituted phenyl,

b) R⁷ is phenyl, phenyl substituted by 1 to 3 substituents [wherein thesubstituents independently of one another denote halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃ or OCF₃], piperidinyl,1-methylpiperidinyl,

 if R⁸ is H, —CONH₂, —N(CH₃)C(O)CH₃, CN

 or —C(O)N((C₁₋₃)alkyl)₂

or

c) R⁷ and R⁸ together form the group

R₃ denotes H, (C₁₋₄)alkyl, unsubstituted or mono- to tri-substitutedphenyl, wherein the substituents independently of one another representhalogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁷R¹⁸(wherein R¹⁷ and R^(˜)independently of one another denote H, muethyl oracetyl);

R⁴ denotes phenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, wherein phenyl manybe substituted by 1 to 3 substituents, wherein the substituentsindependently of one another are halogen (F, Cl, Br, I), (C₁₋₄)alkyl,O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰ independentlyof one another denote H, methyl or acetyl);

and

R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆) cycloalkyl, CH₂COOH, —CH₂C(O)NH₂, —OHor phenyl (C₁₋₄)alkyl.

The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have both substance P-antagonism and alsoneurokinin A- or neurokinin B-antagonistic properties. They are usefulfor the treatment and prevention of neurokinin-mediated diseases.

Compounds of general formula I may contain acid groups, chiefly carboxylgroups, and/or basic groups such as, for example, amino functions.Compounds of general formula I may therefore be obtained either asinternal salts, as salts with pharmaceutically acceptable inorganicacids such as hydrochloric acid, sulphuric acid, phosphoric acid orsulphonic acid or organic acids (such as, for example, maleic acid,fumaric acid, citric acid, tartaric acid or acetic acid) or as saltswith pharmaceutically acceptable bases such as alkali or alkaline earthmetal hydroxides or carbonates, zinc or ammonium hydroxides or organicamines such as, for example, diethylamine, triethylamine ortriethanolamine, etc.

The compounds according to the invention may occur as racemates but mayalso be obtained as pure enantiomers, i.e. in (R)- or (S)-form. They mayalso occur as diastereoisomers or mixtures thereof.

The preferred compounds of general formula I are those wherein

R¹ and R² together with the N to which they are bound form a 6-memberedring of the formula

 wherein

X denotes N(CH₂)_(n)R⁶ or CR⁷R⁸, wherein n, R⁶, R⁷ and R⁸ are defined asin claim 1.

Particular mention should be made of compounds of formula I wherein

x is N(CH₂)_(n)R⁶ wherein n is 0, 1 or 2 and R⁶ is (C₃₋₇)cycloalkyl orphenyl, particularly those compounds wherein n is 0 and R⁶ is(C₃₋₇)cycloalkyl, particularly those compounds wherein R₆ is cyclobutylor cyclohexyl.

Mention should also be made of compounds of formula I wherein

R⁷ and R⁸ have one of the following meanings:

a) R⁷ and R⁸ denote H when R³ is unsubstituted or substituted phenyl,

b) R⁷ is phenyl, piperidinyl

 if R⁸ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃ or CN,—

or

c) R⁷ and R⁸ together form the group

 particularly those wherein

R⁷ and R⁸ have one of the following meanings:

a) R⁷ and R⁸ denote H when R³ is unsubstituted or substituted phenyl,

b) R⁷ is phenyl,

 when R⁸ is H, —CONH₂ or CN,

or

c) R⁷ and R⁸ together form the group

The preferred compounds are those wherein

R⁷ denotes phenyl,

 and R⁸ is H or CN, particularly those wherein R⁷ is pyridino and R⁸ isH.

Of the compounds defined above, the preferred ones are those wherein

Ar denotes unsubstituted or mono- or di-substituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br, I), OH, methyl,methoxy, CF₃, OCF₃ or dimethylaminel or Ar is phenyl substituted by—OCH₂O—, this group connecting positions 2 and 3 or 3 and 4 of thephenyl, particularly those wherein

Ar denotes unsubstituted or mono- or di-substituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br), methoxy or CF₃] orAr is phenyl substituted by —OCH₂O—, this group connecting positions 2and 3 or 3 and 4 of the phenyl.

The preferred compounds are those wherein Ar is phenyl,3,4-dichlorophenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl.

Of the compounds defined above, particular mention should be made ofthose wherein R³ is phenyl or preferably H.

Of the compounds defined above, mention should also be made of thosewherein

R⁴ denotes phenyl(C₁₋₃)alkyl, wherein phenyl may be substituted by 1 or2 substituents, the substituents independently of one another beinghalogen (F, Cl, Br, I), methyl, methoxy, CF₃ or OCF₃;

and

R⁵ denotes H, (C₁₋₃)alkyl, CH₂COOH, —CH₂C(O)NH₂ or phenethyl,

particularly those compounds wherein

R⁴ is

and R⁵ denotes H or CH₃.

The following compounds are preferred:

The term naphthyl used above includes both 1-naphthyl and 2-naphthyl.

Test results for compounds according to the invention:

The receptor affinity for the NK₁-receptor (substance P-receptor) isdetermined on human lymphoblastoma cells (IM-9) with clonedNK₁-receptors, measuring the displacement of ¹²⁵I-labelled substance P.The K_(i)-values thus obtained demonstrate the efficacy of thecompounds:

K_(i) Compound of Example 3: 1.4 nM Compound of Example 4: 1.0 nMCompound of Example 5: 1.3 nM Compound of Example 33: 1.3 nM Compound ofExample 45: 1.6 nM Compound of Example 46: 1.4 nM Compound of Example52: 1.1 nM Compound of Example 53: 2.3 nM Compound of Example 58: 6.4 nMCompound of Example 59: 4.2 nM Compound of Example 65: 9.2 nM Compoundof Example 66: 1.4 nM Compound of Example 68: 1.5 nM Compound of Example70: 2.8 nM Compound of Example 71: 2.1 nM Compound of Example 72: 6.8 nMCompound of Example 73: 1.7 nM Compound of Example 74: 11.8 nM Compoundof Example 75: 180 nM Compound of Example 76: 7.0 nM

The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have, in particular, NX₁-antagonism, butalso NK₂— and NK₃-antagonistic properties.

The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have both substance P-antagonism and alsoneurokinin A- or neurokinin B-antagonistic properties. They are usefulfor the treatment and prevention of neurokinin-mediated diseases:treatment and prevention of inflammatory and allergic diseases of therespiratory tract, such as asthma, chronic bronchitis, emphysema,rhinitis or coughs, eye diseases such as conjunctivitis and iritis, skindiseases such as dermatitis in contact eczema, urticaria, psoriasis,sunburn, insect bites and stings, neurodermitis, itching andpostherpetic pain,

diseases of the gastrointestinal tract such as gastric and duodenalulcers, ulcerative colitis, Crohn's disease, irritable bowel,Hirschsprung's disease;

diseases of the joints such as rheumatoid arthritis, reactive arthritisand Reiter syndrome;

for treating diseases of the central nervous system such as dementia,Alzheimer's disease, schizophrenia, psychosis, depression, headaches(e.g. migraine or tension headaches) and epilepsy;

for the treatment of tumours, collagenosis, dysfunction of the urinarytract, haemorrhoids, nausea and vomiting, triggered for example byradiation or cytostatic therapy or motion and pain of all kinds.

The invention therefore also relates to the use of the compoundsaccording to the invention as remedies and pharmaceutical preparationswhich contain these compounds. They are preferably for use in humans.The compounds according to the invention may be administered byintravenous, subcutaneous, intramuscular, intraperitoneal or intranasalroute or by inhalation, by transdermal route, if desired with the aid ofiontophoresis or enhancers known from the literature, and by oral route.

For parenteral administration, the compounds of formula I or thephysiologically acceptable salts thereof, optionally with conventionalsubstances such as solubilisers, emulsifiers or other adjuvants, may bemade into solutions, suspensions or emulsions. Suitable solventsinclude, for example, water, physiological saline solutions or alcohols,e.g. ethanol, propanediol or glycerol, sugar solutions such as glucoseor mannitol solutions or a mixture of various solvents.

In addition, the compounds may be administered by means of implants,e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or bymeans of intranasal preparations.

The oral effectiveness of compounds of general formula I can bedemonstrated using the following standard test:

Inhibition of the lowering of blood pressure caused by NK₁ inanaesthetised guinea pigs.

Guinea pigs weighing 300-500 grams were anaesthetised with pentobarbital(50 mg/kg i.p.), intubated and mechanically ventilated with 10 ml ofambient air per kg of body weight at a rate of 60 breaths per minute.The blood pressure was measured in the blood flow through the carotidartery. In order to introduce substances intravenously, the jugular veinwas cannulated.

By the intravenous administration of the NK₁-agonist [βAla⁴, Sar⁹,Met(O₂)¹¹] SP(4-11) (0.2 μmol/kg) a brief lowering of the blood pressurewas triggered which was repeated at 10 minute intervals by repeatedlygiving the NK₁-agonist.

The neurokinin-antagonist was then administered by intraduodenal routeand at 10 minute intervals a lowering of blood pressure was induced bymeans of the NK₁-agonist.

The inhibition of the lowering of blood pressure caused by theabove-mentioned NK₁-agonist was measured before and after treatment withthe neurokinin-antagonist.

The compound of Example 5 yielded an ID₅₀ of 1.4 mg/kg. (ID₅₀ is thedose which inhibits the lowering of blood pressure caused by theNK₁-agonist by 50%.)

The compounds according to the invention may be prepared by generallyknown methods.

The compounds may be prepared in various ways. The two commonest methodsare shown in the following scheme:

Method A. The carboxylic acid may be linked to the amine HN(R⁵)R⁴ invarious ways. The usual methods are coupling methods such as those usedin peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, CDI,etc., is added to the coupling partners in an approximately equivalentamount. Suitable solvents are DMF, THF CH₂Cl₂, CHCl₃ acetonitrile orother inert solvents or mixtures thereof. The appropriate temnperaturerange is between −50° C. and +120° C., preferably between 0° C. and 40°C.

The carboxylic acid may also initially be converted by means ofSOCl₂SO₂Cl₂, PCl₃, PCl₅ or PBr₃ or mixtures thereof, by known methods,into the corresponding acid halide which is subsequently reacted withthe amine HN(R⁵)R⁴ in an inert solvent such as CH₂Cl₂, THF or dioxane attemperatures between −50° C. and +100° C., typically between 0° C. and20° C.

Another alternative is to convert the carboxylic acid initially into thealkylester, usually the methylester, by known methods and then to reactthis ester with the amine HN(R⁵)R⁴ in an inert solvent such as DMF,dioxane or THF. The reaction temperatures are between 20° C. and 150°C., typically between 50° C. and 120° C. The reaction may also becarried out in a pressurised container.

Process B. In this, the α-halo-arylacetamide derivative obtainedaccording to known procedures is reacted with the amine R¹(R²)NH,thereby generating hydrogen halide. In order to mop up the cleaved (orexcess) hydrogen halide, inorganic bases are used such as K₂CO₃, NaHCO₃or CaCO₃, or organic bases may be used such as triethylamine, Hünigbase, pyridine or DMAP, or an excess of the amine R¹(R²)NH may be used.DMF, THF, dioxane or other inert solvents are used. The temperaturerange for the reaction is from 0 to 100° C., typically from 10 to 80° C.

Process C. The compounds according to the invention in which R⁵ is not Hmay also be prepared as follows: first of all, the correspondingcompound in which R⁵ is H is synthesised according to process A or B.Then N-alkylation is carried out as follows in order to introduce alkyl,cycloalkyl or CH₂COOH. The compound according to the invention whereinR⁵ is H is deprotonated with an equivalent quantity of NaH, NaNH₂, KOH,NaOCH₃ or some other strong base. Anhydrous inert solvents such as THF,dioxane or diethylether are used. Then the corresponding alkylatingagent is added slowly in the form of the corresponding halide, tosylateor mesylate. The reaction is carried out in the temperature range from−50° C. to +100° C., typically between 0° C. and +50° C. The method isdescribed in detail in Example 33.

EXAMPLES Example 1:

1st Step: 2.2 g of 1-cyclohexylpiperazine were dissolved in 150 ml ofanhydrous DMF, mixed with 2 g of K₂CO₃, stirred at room temperature for20 minutes and then cooled to 5° C. 2.7 g of methyl(R,S)-α-bromophenylacetic acid were added and the suspension was stirredovernight at RT. The precipitate was filtered off and the filtrate wasevaporated down. The residue was taken up in ethyl acetate, extractedtwice with 10% KHCO₃ solution and once with saturated NaCl solution. Theorganic phase was dried over Na₂SO₄, filtered and evaporated down, and3.7 g of (R,S)-1-cyclohexyl-4-(methyl 2-phenylacetate)-piperazine wereobtained in the form of a yellow oil. Yield: about 100%.

2nd Step: 2.3 g of the product of the first step were dissolved in 10 mlof methanol, mixed with 14 ml of 1N NaOH and the resulting emulsion wasstirred overnight at room temperature. The clear reaction solution wasneutralised by the addition of 14 ml of 1N HCl, evaporated to dryness,the residue was treated with isopropanol and the solid matter wascollected by suction filtration. The filtrate was evaporated down andthe residue was triturated again with isopropanol, the solid matter wassuction filtered and combined with the solid obtained earlier. In thisway, 1.6 g of (R,S)-1-cyclohexyl-4-(2-phenylacetic acid)-piperazine wereobtained as a white solid. Yield: 75%.

3rd Step: 0.6 g of the product of the second step, 0.48 g of3,5-bis-(trifluoromethyl)-benzylamine and 0.32 g of HOBT were suspendedin 60 ml of THF/CH₂Cl₂ (1:1) and adjusted to pH 8.5 by the addition ofabout 0.7 ml of Hünig base. 0.77 g of TBTU were added and the mixturewas stirred overnight at room-temperature. The clear reaction solutionwas evaporated down in vacuo, the residue was taken up in CH₂Cl₂ andextracted twice with 10% KHSO₄ solution, once with saturated NaClsolution, twice with 10% KHCO₃ solution and once more with saturatedNaCl solution. The organic phase was dried over Na₂SO₄, filtered andevaporated down, whereupon crystallisation took place. 0.685 g of(R,S)-1-cyclohexyl-piperazinyl-4-(2-phenylaceticacid-N-(3,5-bis-trifluoromethylbenzyl)amide] were obtained as ayellowish solid. Yield 64%.

Mp: 124-129° C. FAB-MS: (M+H)⁺=528.2.

Example 2

1st Step: 0.49 g of 3,5-bis-(trifluoromethyl)-benzylamine were dissolvedin 30 ml of anhydrous CH₂Cl₂, 0.3 ml of triethylamine were added, themixture was cooled in an ice bath and over 20 minutes a solution of 0.46g of (R,S)-α-bromophenylacetyl chloride in 10 ml of CH₂Cl₂ was addeddropwise. After the mixture had stood at room temperature over aweekend, the solvent was eliminated and the solid residue was trituratedwith diethylether, suction filtered and the filtrate was evaporateddown. 0.6 g of α-bromophenylacetic acidN-(bis-trifluoromethyl-benzyl)-amide were obtained as a light beigesolid. Yield: 43.5%.

2nd Step: 0.21 g of 4-propionylamino-piperidine hydrochloride weredissolved in 30 ml of anhydrous DMF, 0.33 g of K₂CO₃ were added and themixture was stirred for 30 minutes at room temperature. Over 20 minutesa solution of 0.68 g of the product of the first step in 10 ml of DMFwere added dropwise to this mixture, which was then stirred overnight atroom temperature. The suspension was filtered, the filtrate wasevaporated down, the oily residue obtained was taken up in ethylacetate, extracted twice with 10% KHCO₃ solution and once with saturatedNaCl solution. The organic phase was dried over Na₂SO₄, filtered, thefiltrate was evaporated down and the semi-solid residue obtained wastriturated with diethylether and suction filtered. 0.33 g of(R,S)-4-propionylamino-1-[2-phenylaceticacid-N(3,5-bis-trifluoromethyl-benzyl)-amide]-piperidine were obtainedas a white solid.

Yield: 64% Mp: 189-191° C. FAB-MS: (M+H)⁺=516.4.

Example 33

Mp: >240° C.; FAB-MS: (M+H)⁺=556.4

0.3 g of the compound according to Example 25 were converted into thecorresponding base by treatment with KHCO₃ and dried. The resultingproduct was dissolved in 5 ml of anhydrous THF, 34 mg of NaH (60% inoil) were added and the mixture was stirred for 1.5 hours at roomtemperature. Then 0.1 g of methyliodide were added and the mixture wasstirred overnight. The reaction mixture was mixed with 2 ml of THF/water(1:1) then with 25 ml of water and extracted 3 times with ether. Thecombined ether extracts were dried over Na₂SO₄ and evaporated down invacuo, thereby obtained 170 mg of the desired compound in the form of afree base (oil). This was converted into the dihydrochloride by theaddition of an excess of ethereal HCl, the dihydrochloride beingobtained in the form of yellow crystals. Yield: 113 mg (36%).

The other compounds of the invention may be prepared analogously, e.g.as follows:

Example 3

Mp: 235-238° C. FAB-MS: (M+H)⁺=542.2.

Example 4

Mp: >240° C. (Decomp.). FAB-MS: (M+H)⁺=542.3.

Example 5

Mp: 158-164° C.; FAB-MS: (M+H)⁺=556.4.

Example 6

Mp: 97-99° C.; FAB-MS: (M+H)⁺=556.3.

Example 7

Mp: >240° C. (Decomp.); FAB-MS: (M+H)⁺=528.4.

Example 8

Mp: 102-105° C.; FAB-MS (M+H)⁺=640.3.

Example 9

Mp: 141-149° C; FAB-MS: (M+H)⁺=579.2.

Example 10

Mp: 218-223° C; FAB-MS: (M+H)⁺=579.3.

Example 11

Mp: >220° C. (Decomp.); FAB-MS (M+H)⁺=571.3

Example 12

Mp: 205-210° C.; FAB-MS: (M+H)⁺=591.3.

Example 13

Mp: 87-95° C.; FAB-MS: (M+H)⁺=571.2

Example 14

Mp: 164-166° C.; FAB-MS: (M+H)⁺=537.3.

Example 15

Mp: 208-210° C.; FAB-MS: (M+H)⁺=578.3

Example 16

Mp: 110-115° C.; FAB-MS: (M+H)⁺=542.3.

Example 17

Mp: 118-123° C.; FAB-MS: (M+H)⁺=556.3

Example 18

Mp: 134-136° C.; FAB-MS: (M+H)⁺=514.3

Example 19

Mp: >240° C. (Decomp.): FAB-MS: (M+H)⁺=564

Example 20

Mp: 180-185° C.; FAB-MS: (M+H)⁺=564.3

Example 21

Mp: 228-232° C.; FAB-MS: (M+H)⁺=606/608

Example 22

Mp: 70-73° C.; FAB-MS: (M+H)⁺=586

Example 23

Mp: 248-254° C.; FAB-MS: (M+H)⁺=596/598/600

Example 24

Mp: 210° C.; FAB-MS: (M+H)⁺=664.1

Example 25

Mp: 192-199° C.; FAB-MS: (M+H)⁺=542.3

Example 26

Mp: 112-118° C.; FAB-MS: (M+H)⁺=562/564

Example 27

Mp: 124-127° C.; FAB-MS: (M+H)⁺=606/608

Example 28

Mp: 118-120° C.; FAB-MS: (M+H)⁺=606/608

Example 29

Mp: 120-122° C.; FAB-MS: (M+H)⁺=562/564

Example 30

Mp: >240° C.; FAB-MS: (M+H)⁺=562/564

Example 31

Mp: >240° C.; FAB-MS: (M+H)⁺=546.3

Example 32

Mp: 125-130° C. (Decomp.) FAB-MS: (M+H)⁺=610.4

Example 33

MP: 240° C.; FAB-MS: (M+H)⁺=556.4

Example 34

Mp: 145-151° C.; FAB-MS: (M+H)⁺=641.3

Example 35

Example 36

Mp: 175-176.5° C.

Example 37

Mp: 157-158° C.

Example 38

Mp: 155-172° C. FAB-MS: (M+H)⁺=592.2

Example 39

Example 40

Example 41

Example 42

Mp: 142-150° C. FAB-MS: (M+H)⁺=558.2

Example 43

Example 44

Mp: 107-111° C.; FAB-MS: (M+H)⁺=575.6

Example 45

Mp: >230° C.

Example 46

Mp: >230° C.

Example 47

Mp: 127-137° C. FAB-MS: (M+H)⁺=592

Example 48

Example 49

Example 50

Mp. 106-110° C. FAB-MS: (M+H)⁺=549.4

Example 51

Example 52

Mp: 133-143° C. FAB-MS: (M+H)⁺=542.3

Example 53

Mp. 110-120° C. FAB-MS: (M+H)⁺=570.4

Example 54

Example 55

Example 56

Example 57

Example 58

Mp: 212-216° C. (Decomp.) FAB-MS: (M+H)⁺=624.3/626.3/628.3

Example 59

Mp: 244-246° C. (Decomp.) FAB-MS: (M+H)⁺=624.1/626.2/628

Example 60

Mp: 113-123° C. FAB-MS: (M+H)⁺=550.3

Example 61

Mp: 195-205° C.

Example 62

Mp: 210-218° C. FAB-MS: (M+H)⁺=620/622

Example 63

Mp: 215-224° C. FAB-MS: (M+H)⁺=576/578

Example 64

Mp: 85-92° C. FAB-MS: (M+H)⁺=572.5

Example 65

Mp: 148-156° C. FAB-MS: (M+H)⁺=578.4

Example 66

Mp: 113-117° C. (decomp.) FAB-MS: (M+)⁺=528.5

Example 67

Mp: 265-268° C. (decomp.) FAB-MS: (M+H)⁺=619.3

Example 68

Mp: 236-238° C. (decomp.) FAB-MS: (M+H)⁺=528.3

Example 69

Mp: 177-187° C. FAB-MS: (M+H)⁺=605.3

Example 70

Mp: 123-133° C. (decomp.) FAB-MS: (M+H)⁺=616.3

Example 71

Mp: 87-97° C. FAB-MS: (M+H)⁺=600.2

Example 72

Mp: >230° C.

Example 73

Mp: >230° C.

Example 74

Mp: >230° C.

Example 75

Mp: 91-98° C. FAB-MS: (M+H)⁺=574.4

Example 76

Mp: 234-236° C.

Example 77

Mp: 195-198° C.

Example 78

Pharmaceutical Preparations:

Injectable solution 200 mg of active substance* 1.2 mg of monopotassiumdihydrogen phospate = ) KH₂PO₄ 0.2 mg of disodium hydrogen phosphate = )(buffer) NaH₂PO₄.2H₂O ) 94 mg of sodium chloride ) or ) (isotonic) 520mg of glucose ) 4 mg of albumin (protease protection) q.s. sodiumhydroxide solution ) q.s. hydrochloric acid ) to adjust the pH to pH 6

sufficient water to. make a 10 ml solution for injection

Injectable solution 200 mg of active substance* 94 mg of sodium chlorideor 520 mg of glucose 4 mg of albumin q.s. sodium hydroxide solution )q.s. hydrochloric acid ) to adjust the pH to pH 9

sufficient water to make a 10 ml solution for injections lyophilisate

Lyophilisate 200 mg of active substance* 520 mg of mannitol(isotonic/structural component) 4 mg of albumin Solvent 1 forlyophilisate 10 ml of water for injections Solvent 2 for lyophilisate 20mg of Polysorbate ®80 - Tween ®80 (surfactant) 10 ml of water forinjections *Active substance: compound according to the invention, e.g.that of Examples 1 to 78.

Dosage for humans weighing 67 kg: 1 to 500 mg

What is claimed is:
 1. An arylglycinamide derivative of formula I:

or a pharmaceutically acceptable salt thereof, wherein Ar isunsubstituted or mono- to penta-substituted phenyl, or unsubstituted ormono- or di-substituted naphthyl, in which the substituents of thephenyl and naphthyl are independently selected from the group consistingof halogen, hydroxy, (C,₁₋₄)alkyl, O—(C ₁₋₄)alkyl, CF₃, OCF₃ and NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently selected from the group consistingof hydrogen, methyl and acetyl; or Ar is phenyl substituted by —O—CH₂—O—or —O—(CH₂)₂—O—; R¹ and R² together with the N to which they are boundform a zing of the formula

 wherein p is 2or 3; X is CR⁷R⁸;

R₈ is hydrogen, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, CN,—C(O)NH(C₁₋₃)alkyl, or —C(O)N((C₁₋₃)alkyl)₂; R³ is hydrogen,(C₁₋₄)alkyl, unsubstituted phenyl or mono- to tri-substituted phenyl,wherein the substituents are independently selected from the groupconsisting of halogen, (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ and NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently selected from the group consistingof hydrogen, methyl and acetyl; R⁴ is phenyl (C₁₋₄)alkyl ornaphthyl(C₁₋₄)alkyl, wherein phenyl is optionally substituted by 1 to 3substituents independently selected from the group consisting ofhalogen, (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ and NR9R¹⁰, wherein R⁹and R¹⁰ are independently selected from the group consisting ofhydrogen, methyl and acetyl; and R⁵ is hydrogen, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, CH₂COOH, —CH₂C(O)NH₂, hydroxy or phenyl (C₁₋₄)alkyl.2. The compound of claim 1, wherein R⁷ is


3. The compound of claim 2, wherein said compound is

or the HCl salt thereof.
 4. The compound of claim 1, wherein R⁷ is


5. The compound of claim 4, wherein said compound is

or the HCl salt thereof.
 6. The compound of claim 5, wherein saidcompound is


7. The compound of claim 1, wherein R⁷ is


8. The compound of claim 7, wherein said compound is

or the HCl salt thereof.
 9. The compound of claim 1 wherein R⁷ is4-morpholino.
 10. The compound of claim 9, wherein said compound is

or the HCl salt thereof.
 11. The compound of claim 10, wherein saidcompound is


12. The compound of claim 1, wherein R⁷ is 1-piperidinyl.
 13. Thecompound of claim 12, wherein said compound is

or the HCl salt thereof.
 14. The compound of claim 13, wherein sadcompound is


15. The compound of claim 1, wherein R⁷ is


16. The compound of claim 15, wherein said compound is

or the HCl salt thereof.
 17. The compound of claim 1, wherein R⁷ is1-pyrrolidinyl.
 18. The compound of claim 17, wherein said compound is

or the HCl salt thereof.
 19. The compound of claim 18, wherein saidcompound is


20. The compound of claim 1, wherein Ar is phenyl having 0, 1, 2 or 3substituents.
 21. The compound of claim 1, wherein R³ is hydrogen ormethyl.
 22. The compound of claim 1, wherein R³ is unsubstituted phenyl.23. The compound of claim 1, wherein R³ is mono- to tri-substitutedphenyl.
 24. The compound of claim 1, wherein R⁴ is phenyl (C₁₋₃)alkyl,wherein said phenyl is optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of halogen, methyl,methoxy, CF₃ and OCF₃; and R⁵ is selected from the group consisting ofhydrogen (C₁₋₃)alky, CH₂COOH, —CH₂C(O)NH₂ and phenethyl.
 25. Thecompound of claim 24, wherein R⁴ is

R⁵ is hydrogen or methyl.
 26. The compound of claim 1, wherein R⁵ ishydrogen or (C₁₋₄)alkyl.
 27. The compound of claim 1, wherein R⁸ ishydrogen.
 28. The compound of claim 1, wherein R⁸ is selected from thegroup consisting of —NHC(O)CH₃ and —N(CH₃)C(O)CH₃.
 29. The compound ofclaim 1, wherein R⁸ is selected from the group consisting of CN,—C(O)NH₂, —C(O)NH(C₁₋₃)alkyl and —C(O)N((C₁₋₃)alkyl)₂.
 30. Apharmaceutical composition, comprising the compound of claim 1, and apharmaceutically acceptable carrier.
 31. The pharmaceutical compositionof claim 30, which is in the form of a solution, suspension or emulsion.32. The pharmaceutical composition of claim 30, wherein said carrier isa polylactide, polyglycolide or polyhydroxybutyric acid.
 33. Thepharmaceutical composition of claim 30, which is an orally administrablepharmaceutical composition.
 34. A method for the treatment of aneurokinin-mediated disease in an animal subject comprisingadministering to said animal subject in need of such treatment aneffective amount of the compound of claim
 1. 35. The method of claim 34,wherein said neurokinin-mediated disease is selected from the groupconsisting of collagenosis, dysfunction of the urinary tract,hemorrhoids, nausea, vomiting, and pain.
 36. The method of claim 34,wherein said neurokinin-mediated disease is an inflammatory disease ofthe respiratory tract, an allergic disease of the respiratory tract, aneye disease, a skin disease, a disease of the gastrointestinal tract, adisease of the joints, or a disease of the central nervous system. 37.The method of claim 34, wherein said neurokinin-mediated disease is aninflammatory or allergic disease of the respiratory tract selected fromthe group consisting of asthma, chronic bronchitis, emphysema, rhinitisand coughs.
 38. The method of claim 34, wherein said neurokinin-mediateddisease is an eye disease selected from the group consisting ofconjunctivitis and iritis.
 39. The method of claim 34, wherein saidneurokinin-mediated disease is a skin disease selected from the groupconsisting of eczema, urticaria, psoriasis, sunburn, insect bites,insect stings, neuroderm-ititis, itching and postherpetic pain.
 40. Themethod of claim 34, wherein said neurokinin-mediated disease is adisease of the gastrointestinal tract selected from the group consistingof gastric and duodenal ulcers, ulcerative colitis, Crohn's disease,irritable bowel and Hirschsprung's disease.
 41. The method of claim 34,wherein said neurokinin-mediated disease is a disease of the jointsselected from the group consisting of rheumatoid arthritis, reactivearthritis and Reiter syndrome.
 42. The method of claim 34, wherein saidneurokinin-medated disease is a disease of the central nervous systemselected from the group consisting of dementia, Alzheimer's disease,schizophrenia, psychosis, depression, headaches and epilepsy.
 43. Themethod of claim 42, wherein said disease is a migraine headache or atension headache.
 44. The method of claim 34, wherein said administeringis orally administering.
 45. A process for preparing a compound of claim22, comprising the steps of: (a) reacting a compound of formula

 or an acid halide or alkylester thereof with an amine of formula

 wherein R¹-R⁵ and Ar are defined as in claim 1; and (b) isolating theproduct of step (a) as a free compound or as a pharmaceuticallyacceptable salt thereof.
 46. A process for preparing a compound of claim1, comprising the steps of: (a) reacting a compound of formula

 or an acid halide or alkylester thereof with an amine of formula

 wherein R¹-R⁴ and Ar are defined as in claim 22 and R⁵ is hydrogen; (b)N-alklating, at R⁵, the product of step (a); and (c) isolating theproduct of step (b) as a free compound or as a pharmaceuticallyacceptable salt thereof.
 47. A process for preparing a compound of claim1, comprising the steps of: (a) reacting a compound of formula

 with an amine of formula

 wherein R¹-R⁵ and Ar are defined as in claim 1 and Hal is halogen; and(b) isolating the product of step (a) as a free compound or as apharmaceutically acceptable salt thereof.
 48. A process for preparing acompound of claim 1, comprising the steps of: (a) reacting a compound offormula

 with an amine of formula

 wherein R¹-R⁴ and Ar are defined as in claim 1, R⁵ is hydrogen and Halis halogen; (b) N-alkylating, at R⁵, the product of step (a); and (c)isolating the product of step (b) as a free compound or as apharmaceutically acceptable salt thereof.